1. Field of the Invention
The present invention relates to triaging or sorting and selecting substances for their capacity for sebosuppressive activity in topical skin treatments. The invention also concerns substances identified from such triaging or sorting.
The present invention relates more particularly to a topical pharmaceutical composition for the treatment and/or prevention of hyperseborrhea and associated seborrheic skin disorders such as acne and seborrheic dermatitis.
2. Description of the Prior Art
The aryl hydrocarbon Receptor (AhR) is a transcription factor, which induces the expression of some genes while inhibiting the expression of other genes. A significant number of ligands, both naturally occurring ligands present in foods, as well as xenobiotics, have been reported to interact with this receptor (Abel et al. (2010)). AhR is typically expressed in epithelial and mesenchymal skin cells, as well as in other cell types (Ikuta et al. 2009). International Patent Publications WO 2004/041758 and WO 2007/128725 and U.S. Patent Application Publication No. 2009/0028804 A1 describe certain in vitro tests to determine the antagonist or agonist nature of such ligands.
The prototypical xenobiotic agonist ligand of the AhR is the notorious environmental toxin 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), better known simply as “dioxin” (Mandal (2005)). Other xenotoxic compounds which interact as agonists with the AhR are also capable of causing various types of damaging tissue lesions. Multiple toxic effects are known. The most visible are the cystic lesions formerly called “chloracne” but which have more recently been redefined as MADISH (Saurat et al. (2012)). For this reason, the use of AhR pathway agonists in a therapeutic and/or preventative context as active agents that beneficially modulate skin function is counter-intuitive. Indeed, International Patent Publications WO 2004/041758 and WO 2007/128725 propose to use AhR antagonists rather than agonists to treat various dermatological conditions, including acne.
U.S. Patent Application Publication No. 2010/0324109 A1 suggests that the application to the skin of certain AhR receptor pathway agonists may favorably modulate some skin functions such as sebaceous gland function, acne, defense against infection, wound healing, and skin atrophies which involve dermatoporosis and estrogen deprivation. However, to achieve a therapeutic window between the beneficial application of certain AhR pathway agonists and the detrimental effects of other AHR pathway agonists, such as TCDD, certain properties must be selected for.
It is currently unknown how to best identify suitable candidates from AhR agonists that are likely to be endowed with sebosuppressive properties and likely to be therapeutically beneficial to man. Currently available approaches comprise prolonged dosing with atrophy-inducing tests of the differentiated regions of the sebaceous glands in suitable animal species. These tests involve complex histological interpretation and, in addition, typically require the prolonged chronic application of the ligands under consideration.
It is therefore an objective of this invention to propose a triage or sorting method that is rapid, sensitive and predictive of human efficacy with respect to sebosuppressive properties on human skin. This invention thus provides a novel method to identify sebum reducing AhR pathway agonists useful to treat certain skin diseases, and novel pharmaceutical compositions useful for treating disorders related to abnormal metabolism mediated by the AhR receptor.